Prostate cancer is the most common malignancy in males other than skin cancer and is the second leading cause of cancer death in men. Prostate cancer growth in most patients is androgen dependent, so that removing androgens (androgen ablation) by orchiectomy or the administration of LHRH agonists is a very effective treatment. Unfortunately, most patients develop androgen-independent (AI) prostate cancer within two years, for which there is no effective treatment. The mechanisms by which tumor cells escape androgen ablation and become androgen-independent are unknown. However, several lines of evidence indicate that mutations in the androgen receptor (AR), which mediates the effects of androgens on prostate cells, may be one important mechanism. The specific aims of this project are 1) to determine the frequency and spectrum of AR mutations in AI prostate cancer and 2) to determine the functional significance of these mutations. The AR from a series AI prostate cancer patients will be analyzed by reverse transcription- polymerase chain reaction amplification, using involved bone marrow as the primary source of tumor. Mutations will be identified primarily by DNA sequencing of multiple ARs from each patient. The potential functional significance of AR mutations will be assessed by determining their affinity for a series of steroid hormones and their ability to transactivate a reporter gene linked to an androgen responsive element. Studies will also be initiated to identify drugs which can inhibit mutants ARs. The goal will be to establish whether and by what mechanisms AR mutations play a role in the development of AI prostate cancer. If successful, then these mutant ARs may be useful as targets in the development of new drugs for the treatment of prostate cancer.